NEW YORK (GenomeWeb) – An international team of researchers has identified hundreds of potential causal variants associated with various blood traits and tied these variants to mechanisms through which they may have their effects.
After performing a genome-wide association study of more than a dozen blood cell traits using the UK Biobank dataset, researchers led by Harvard Medical Schools' Vijay Sankaran conducted a fine-mapping analysis and devised a new method, dubbed genetic-chromVAR (g-chromVAR), to measure the enrichment of fine-mapped variants in different tissues. Based on their analyses, the researchers found that some of the variants they uncovered appeared to tune the production of various hematopoietic cell lineages, a result they reported today in Nature Genetics.
"Overall, our integrated approach is designed to sequentially identify causal genetic variants, their molecular mechanisms, their target genes, and the cell types in which they act," Sankaran and his colleagues wrote in their paper.
The researchers conducted a GWAS using data from about 115,000 people from the UK Biobank that examined 16 different blood cell traits, such as white blood cell count, platelet count, and hemoglobin level. These traits involved seven different hematopoietic lineages, the researchers noted.
To zero in on possible causal variants — a challenge of the post-GWAS era, according to the researchers — the researchers turned to fine mapping to examine more than 2,000 3-Mb-sized regions that contained a genome-wide significant association. In all, they uncovered 38,654 variants that had a more than 1 percent posterior probability of being causal. Additionally, most of the variants with a posterior probability higher than 0.75 also had a minor allele frequency of greater than 5 percent, which they noted was in line with blood traits being polygenic.
Within these variants, the researchers sifted out nonsynonymous and loss-of-function coding variants within genes linked to red blood cell, platelets, monocytes, lymphocytes, and granulocytes, a total 230 genes. Genes the researchers implicated through fine mapping were associated with biologically relevant pathways. For instance, genes linked to red blood cell traits were involved in iron homeostasis, while genes linked to platelet traits were involved in coagulation and wound healing.
Through an ATAC-seq analysis, the researchers likewise uncovered regulatory variants that influence blood cell traits. They also traced these variants to potential biological mechanisms. In all, they linked one or more mechanisms to 145 different fine-mapped noncoding variants.
More than 170 variants the researchers linked to blood cell traits were pleiotropic. The vast majority — 91 percent — of those appeared to represent a tuning mechanism in which two or more different blood cell lineages are influenced at the same time. For instance, they noted that the rs78744187 variant increases red blood cell count while decreasing basophil count. This variant, they noted, is located just downstream of CEBPA, a gene that encodes a myeloid transcription factor.
This suggested to the researchers that these variants could tune or switch the production of different blood cell lineages.
Meanwhile, the researchers developed a new approach that they dubbed genetic-chromVAR — similar to the chromVAR method — to determine the stage of hematopoiesis at which these variants were likely acting. After validating their approach, they gauged which cell types were enriched for each of the 16 blood cell traits. They found, for example, that RBC count was enriched in erythroid precursors, while lymphocyte count was enriched in CD4+ and CD8+ T cells.
At the single-cell level, they further noted that g-chromVAR revealed heterogeneity of genetic enrichment even within cells from the same hematopoietic progenitor populations.